Lymphangiogenesis and Lymphangiogenic Growth Factors

Lymphedema is a progressive disease caused by damage to the lymphatic network. Recent development in the fields of preclinical growth factor research and lymphedema microsurgery promise new hope for lymphedema patients. In this article, we review the latest results on basic research and highlight the role of specific growth factors in normal lymphatic development and several disease states. Lymph node transfer, a new promising method in reconstructive lymphatic microsurgery, is also dependent on the lymphatic vascular regrowth and lymphangiogenic growth factors. We discuss the scientific basis of lymph node transfer and therapeutic potential of lymphangiogenic growth factors in the treatment of lymphedema.Peer reviewe

Somatosensory evoked potentials are abnormal with plagiocephaly

Publisher Copyright: © 2022 Korean Cleft Palate-Craniofacial Association.Background: Deformational plagiocephaly is usually managed conservatively, as it tends to improve over time and with the use of conser-vative measures. However, before the year 2017 we operated on patients with severe plagiocephaly and neurological symptoms at the Helsinki Cleft Palate and Craniofacial Center. Methods: Of the 20 infants with severe deformational plagiocephaly and neurological symptoms referred to us between 2014 and 2016, 10 underwent cranioplasty open reshaping of the posterior cranial vault. The parents of the last 10 patients were given information on the natural history of the condition and the patients were followed up with an outpatient protocol. The aim of this study was to gain information on the brain electrophysiology and recovery of patients after total cranial vault reconstruction by measuring the electroencephalogram (EEG) somatosensory evoked potentials (SEP; median nerve). Results: Of the 10 participants in the operation arm, six had abnormal SEP at least on the affected cerebral hemisphere and all SEPs were recorded as normal when controlled postoperatively. In the follow-up arm, eight out of 10 participants had abnormal SEP at the age of ap-proximately 24 months, and all had normalized SEPs at control visits. Conclusion: Our data suggest that cranioplasty open reshaping of the posterior cranial vault did not affect abnormal SEP-EEG recordings. We have abandoned the operations in deformational plagiocephaly patients due to findings suggesting that expanding cranioplasty is not beneficial for brain function in this patient group.Peer reviewe

Facial asymmetry in children with either unilateral lambdoid craniosynostosis or positional posterior plagiocephaly

Background In unilateral lambdoid craniosynostosis (ULC), the posteriorly situated lambdoid suture of the cranial vault fuses prematurely. Positional posterior plagiocephaly (PPP) causes flattening of the posterior side of the head, either through external forces or through underlying differences in brain development. Both conditions cause occipital flattening of the head, but the aetiology is different. Materials and Methods Eight ULC children were compared with 16 sex- and age-matched PPP children. 3D computer tomography scans of all 24 children were analysed with Dolphin imaging software. The location and symmetry of the temporomandibular joint (Co), and the symmetry of the maxillary anterior nasal spine (ANS) and the mandibular symphysis (Pgn) were analysed. Furthermore, the mandibular bone (Co-Pgn) length, corpus length, ramus height, positional changes in the external acoustic meatus (PoL) and the distance from the orbital margin to the articular fossa were measured. Results In all eight ULC children, the Co was anteriorly displaced on the affected side compared with the unaffected side. In all ULC and PPP children, the ANS, which is considered the bony maxillary midpoint, was shifted towards the affected side. In all ULC children, the mandibular bone (Co-Pgn) was shorter on the affected side. The PoL was antero-inferiorly positioned in all ULC children on the affected side compared with the unaffected side. Conclusions Our results show that both types of posterior plagiocephaly are associated with an asymmetric position of the Co and asymmetry of the mandible and maxilla. Facial asymmetry was more frequently seen in ULC than PPP children.Peer reviewe

Use of black-bone MRI in the diagnosis of the patients with posterior plagiocephaly

Ionising radiation exposure is especially harmful to brain development. The purpose of this study was to evaluate whether black-bone (BB) magnetic resonance imaging (MRI), a non-ionising imaging method, offers an alternative to ionising imaging methods such as computed tomography (CT) in the examination of cranial deformities. From 2012 to 2014, a total of 408 children were referred to the Craniofacial Centre at the Helsinki University Hospital for further examination due to flatness of the posterior skull. Fifteen of these patients required further diagnostic imaging. To avoid ionising radiation, we used an MRI protocol that included sequences for evaluation of both brain anatomy and skull bone and sutures by BB-MRI. A semi-automatic skull segmentation algorithm was developed to facilitate the visualisation. Two patients with scaphocephaly were included in the study to confirm the ability to differentiate synostosis with BB-MRI. We obtained informative 3D images using BB-MRI. Seven patients (7/15, 46.7%) had plagiocephaly on the right side and seven on the left side (7/15, 46.7%). One patient (1/15, 6.7%) had symmetric posterior flatness affecting both sides. Neither structural nor signal-intensity alterations of the brain were detected in visual analysis. BB-MRI provides an alternative to CT when imaging craniofacial deformities. BB-MRI provides not only high-quality 3D-reconstructed imaging of the bony structures and sutures but also information on brain structure in one imaging session. With further development, this method could replace ionising radiation-based methods in analysing deformities of the skull.Peer reviewe

Phase 1 Lymfactin (R) Study : Short-term Safety of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

Objective: To study the safety and tolerability of Lymfactin (R) treatment combined with microvascular lymph node transfer surgery in patients with upper limb lymphedema. Background: Upper limb lymphedema is a common clinical challenge after breast cancer surgery and/or radiotherapy. Lymfactin (R) is an adenovirus type 5-based gene therapy involving expression of human vascular endothelial growth factor C (VEGF-C) in the damaged tissue. It aims to correct deficient lymphatic flow by promoting the growth and repair of lymphatic vessels. Methods: In Phase I, Lymfactin (R) was combined with microvascular lymph node transfer surgery to study the safety and tolerability of Lymfactin (R) and the biodistribution of the viral vector in patients with upper limb lymphedema. Results: Fifteen patients with breast cancer-associated secondary lymphedema of the upper arm were recruited between December 2016 and February 2018. Three patients received a lower dose (1 x 10(10)) and 12 a higher dose (1 x 10(11)) of viral particles, respectively. No dose-limiting toxicities were observed, and the study was completed with the pre-determined maximum dose. Commonly reported adverse events during the 12-month follow-up were common cold, fever, gastroenteritis, pain in the operation area, headache, muscle ache and elevated liver enzymes. Serious adverse events consisted of two erysipelas infections in the lymphedema arm (requiring hospitalization) and one hematoma of the flap donor site. Conclusions: After 12 months' follow-up, results indicate that Lymfactin (R) is well tolerated. The study continues with a 36-months efficacy and 5 years safety follow-up of the patients. The oncological safety aspects of Lymfactin (R) will require a longer follow-up period. (c) 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Pub-lished by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Non-progressive mandibular changes in children with Type I and II craniofacial microsomia

Objective: To describe the mandibular growth of craniofacial microsomia (CFM) patients during early childhood to adolescence with attention to symmetry. Materials and Methods: Altogether 61 CFM patients were studied at the Cleft Palate and Craniofacial Center, Helsinki University Hospital between 1986 and 2006. In this cohort study, we measured and analysed 293 radiographs (posteroanterior, panoramic and lateral); 165 radiographs of 40 patients met the final inclusion criteria. The vertical height of the ramus in anteroposterior and panoramic radiographs, the length of the mandible in anteroposterior radiographs and the maxillary protrusion and mandibular retrognathia in lateral cephalograms were measured in four different age groups. Results: A statistical difference existed between the groups in the vertical height of the ramus and in the mandibular length. The vertical height of the ramus measured from the panoramic radiograph grew on both sides, and the ratios remained unchanged. In the sagittal dimension, the maxilla and mandible grew forward, but no significant differences emerged between the groups. Conclusions: Results suggest that mild-type CFM is not progressive in nature. During growth, mandibular asymmetry measured in the horizontal, vertical and sagittal planes did not increase.Peer reviewe

Short duration of upper extremity lymphedema correlates with a favorable cytokine response after lymph node transfer surgery

Vascularized lymph node transfer surgery (VLNT) can provide benefit to lymphedema patients. Cytokines mayplaya role in the development oflymphedema and in the regeneration oflymphatic vessels after VLNT. Ourprimary aim was to investigate whether the VLNTpatients have a specific cytokine profile. Our secondary aim was to see whether the preoperative lymphedema or severity affects the postoperative cytokine response. Wound exudate was gathered from 18 patients undergoing VLNT on the first and sixth postoperative day (POD). The concentrations of IL-10, TNF-alpha, TGF-beta 1 and VEGF-C were analyzed using enzyme-inked immune-sorbent assays. A general score was generated to assess the benefit ofthe surgery. The changes in cytokine concentrations (1(st) POD-6th POD) were correlated with the pre- andpostoperative lymphedema related factors. A shorter duration oflymphedema preoperatively correlated with an increase in the concentration of IL-10 and TNF-beta during the first six PODs (IL-10: r=0.495, p=0.051; TNF-alpha: p=0.006) and a decrease in the concentration of 7VF-111 (r= p=0.020). The increase ofthe concentration of TNF-alpha during the first six PODs also correlated with a greater total general score (r=0.775, p=0.005) and hence indicated a better response to the surgery. The patients with a shorter duration oflymphedema preoperatively had a more favorable cytokine response during the first six PODs after VLNT

Anti-inflammatory effects of flap and lymph node transfer

Background: Transfer of healthy tissue is commonly used in the treatment of complicated wounds and in reconstruction of tissue defects. Recently, microvascular lymph node transfer (LN) has been used to improve the lymphatic function in lymphedema patients. To elucidate the biological effects of flap transfer (with and without lymph nodes), we have studied the postoperative production of proinflammatory, anti-inflammatory, prolymphangiogenic and antilymphangiogenic cytokines, and growth factors (interleukin 1 alpha [IL-1 alpha], IL-1 beta, tumor necrosis factor alpha [TNF-alpha], IL-10, transforming growth factor beta 1 [TGF-beta 1], IL-4 and IL-13, and vascular endothelial growth factor C [VEGF-C] and VEGF-D) in postoperative wound exudate samples. Methods: Axillary wound exudate samples were analyzed from four patient groups: axillary lymph node dissection (ALND), microvascular breast reconstruction (BR), LN, and combined LN and BR (LN-BR). Results: The concentration of proinflammatory cytokines was low in all the flap transfer groups as opposed to the ALND group, which showed an extensive proinflammatory response. The level of anti-inflammatory and antifibrotic cytokine IL-10 was increased in the LN-BR group samples compared with the ALND and BR groups. In the LN and LN-BR groups, the cytokine profile showed an anti-inflammatory response. Conclusions: Transfer of healthy tissue hinders the proinflammatory response after surgery, which may explain the beneficial effects of flap transfer in various patient groups. In addition, flap transfer with lymph nodes seems to also promote an antifibrotic effect. The clinical effects of LN in lymphedema patients may be mediated by the increased production of prolymphangiogenic growth factor (VEGF-C) and antifibrotic cytokine (IL-10). (C) 2015 Elsevier Inc. All rights reserved.Peer reviewe

Donor-site safety in microvascular lymph node transfer for breast cancer-related lymphedema using reverse lymphatic mapping : A prospective study

Background: Vascularized lymph node transfer (VLNT) is one option among other surgical treatments in the management of breast cancer-related lymphedema (BCRL). The cause of concern regarding VLNT harvested from the groin has been the potential development of secondary lower-extremity lymphedema. This study explored the risks associated with donor-site morbidity following groin VLNT, with or without concomitant breast reconstruction. Method: The cohort comprised data from the Lymfactin® Phase I and II trials, conducted from 2016 to 2019, that used perioperative reverse lymphatic mapping. The volume of the lower extremities was measured preoperatively and at 3, 6, and 12 months postoperative, and the adverse events were documented during study visits. Results: Altogether, 51 women with a mean age of 55.5 years were recruited. The mean duration of BCRL was 31.8 months. Among these, 25 (49%) underwent VLNT (VLNT-group) and 26 (51%) underwent VLNT in combination with breast reconstruction (VLNT-BR group). The groups were similar in terms of age, (p = 0.766), BMI (p = 0.316), and duration of BCRL (p = 0.994). Across a period of one year, the volume difference between the lower extremities changed by 22.6 ml (range: −813 to 860.2 ml) (p = 0.067). None of the patients had lower-extremity volume difference exceeding 10% at the 12-month follow-up visit. The most frequent adverse events were postoperative pain (17.7%), wound healing issues (11.8%), and seroma formation (11.8%). Most adverse events (64.6%) were classified as minor. Conclusions: This prospective study demonstrated that groin VLNT with reverse lymphatic mapping appears safe and does not increase the risk of secondary donor-site lymphedema within one year postoperatively.Peer reviewe

Phase 1 LymfactinⓇ Study: Short-term Safety of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

Objective: To study the safety and tolerability of LymfactinⓇ treatment combined with microvascular lymph node transfer surgery in patients with upper limb lymphedema.Background: Upper limb lymphedema is a common clinical challenge after breast cancer surgery and/or radiotherapy. LymfactinⓇ is an adenovirus type 5–based gene therapy involving expression of human vascular endothelial growth factor C (VEGF-C) in the damaged tissue. It aims to correct deficient lymphatic flow by promoting the growth and repair of lymphatic vessels.Methods: In Phase I, LymfactinⓇ was combined with microvascular lymph node transfer surgery to study the safety and tolerability of LymfactinⓇ and the biodistribution of the viral vector in patients with upper limb lymphedema.Results: Fifteen patients with breast cancer–associated secondary lymphedema of the upper arm were recruited between December 2016 and February 2018. Three patients received a lower dose (1 × 1010) and 12 a higher dose (1 × 1011) of viral particles, respectively. No dose-limiting toxicities were observed, and the study was completed with the pre-determined maximum dose. Commonly reported adverse events during the 12-month follow-up were common cold, fever, gastroenteritis, pain in the operation area, headache, muscle ache and elevated liver enzymes. Serious adverse events consisted of two erysipelas infections in the lymphedema arm (requiring hospitalization) and one hematoma of the flap donor site.Conclusions: After 12 months’ follow-up, results indicate that LymfactinⓇ is well tolerated. The study continues with a 36-months efficacy and 5 years safety follow-up of the patients. The oncological safety aspects of LymfactinⓇ will require a longer follow-up period.</p